Opioid receptors are a group of G-protein coupled receptors that have been identified to have opioids as ligands, which are about 70% identical with differences located at N and C termini of the receptors. Accordingly, opioid drugs have been developed to exploit the biological activity of activating these receptors. Examples of the opioid receptor types, subtypes, location, and agonist activation activities are shown in Table A below. It has been found that modulating the activity of the opioid receptors through an agonist or antagonist can have different therapeutic benefits. Various types of substances, ranging from small molecules through polypeptides, have been explored to identify new drugs that behave as agonists or antagonists of the opioid receptors.
TABLE AReceptorLocationFunctiondelta (δ)BrainanalgesiaOP1(I)pontine nucleiantidepressant effectsamygdalaolfactory bulbsdeep cortexkappa (κ)BrainSpinal analgesiaOP2(I)hypothalamussedationperiaqueductal graymiosisclaustruminhibition of ADHCortexreleaseHippocampusspinal cordsubstantia gelatinosamu (μ)BrainSupraspinal analgesiaOP3(I)cortex (laminae III and IV)respiratory depressionthalamusmiosisstriosomeseuphoriaperiaqueductal grayreduced GI motilityspinal cordsubstantia gelatinosaNociceptinBraintreat heart failurereceptorcortextreat migrainesOP4amygdalaappetitehippocampusdevelopment ofseptal nucleitolerance to μ agonistshabenulahypothalamusspinal cord
In addition to the activation of opioid receptors, inactivation or antagonism of opioid receptors by antagonists can also provide beneficial therapeutic effects. For example, a delta opioid receptor (DOR) antagonist may be useful for treatment for alcoholism and depression. A kappa opioid receptor (KOR) antagonist may be useful for a treatment for drug addiction, depression, inflammation, gastrointestinal, and renal diseases. A mu opioid receptor (MOR) antagonist may be useful for reversing side effects or overdose of a MOR agonist or opioid, obesity, and 1-DOPA induced dyskinesia in Parkinson's Disease. A nociceptin receptor (NR) antagonist may be useful for providing analgesic and antidepressant biological activity.
Other therapeutic benefits and biological activities of opioid receptors continue to be studied. Accordingly, it is important to develop new compounds that have activity with opioid receptors. While traditional chemistry techniques can be applied to creating new compounds, it is also desirable to improve chemical synthesis techniques. This can include simplifying the synthetic chemistry so that compounds can be prepared more easily.
Therefore, it would be advantageous to develop new compounds that were active with opioid receptors. Additionally, it would be beneficial to have improved synthesis techniques so that new compounds can be prepared easier and with more straight forward synthesis protocols.